The Open Translational Science in Schizophrenia (OPTICS) project: an open-science project bringing together Janssen clinical trial and NIMH data.

Clinical trial data are the gold standard for evaluating pharmaceutical safety and efficacy. There is an ethical and scientific imperative for transparency and data sharing to confirm published results and generate new knowledge. The Open Translational Science in Schizophrenia (OPTICS) Project was an open-science initiative aggregating Janssen clinical trial and NIH/NIMH data from real-world studies and trials in schizophrenia. The project aims were to show the value of using shared data to examine: therapeutic safety and efficacy; disease etiologies and course; and methods development. The success of project investigators was due to collaboration from project applications through analyses, with support from the Harvard Catalyst. Project work was independent of Janssen; all intellectual property was dedicated to the public. Efforts such as this are necessary to gain deeper insights into the biology of disease, foster collaboration, and to achieve the goal of developing better treatments, reducing the overall public health burden of devastating brain diseases.

Antibody-based therapeutics: focus on prostate cancer.

The recent clinical and commercial success of anti-cancer antibodies such as rituximab, trastuzumab, cetuximab and bevacizumab has continued to foster great interest in antibody-based therapeutics for the treatment of both hematopoietic malignancies and solid tumors. Given the likely lower toxicity for antibodies which, in contrast with traditional cytotoxic small molecule drugs, target tumor cells and have a lower impact on non-malignant by-stander organs, the potential increases in efficacy associated with conjugation to radioisotopes and other cellular toxins and the ability to characterize the target with clinical laboratory diagnostics to improve the drugs clinical performance, it is anticipated that current and future antibody therapeutics will find substantial roles alone and in combination therapy strategies for the treatment of patients with cancer. A significant number of cell surface proteins, glycoproteins, receptors, enzymes and peptides have been discovered that have become targets for the treatment of advanced hormone-refractory prostate cancer. A variety of naked antibodies and antibody conjugates have currently progressed through preclinical development and are in early or more advanced stages of clinical development. Clinicians, scientists and prostate cancer patients are all keenly interested to learn whether these agents when administered alone or in combination with other hormonal-based and cytotoxic therapies will show lasting benefit for sufferers of this common disease.

Targeted therapy for cancer: the HER-2/neu and Herceptin story.

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. In this article, the association of HER-2/neu gene and protein abnormalities with prognosis and response to therapy with Herceptin and other therapies in breast cancer is presented. By considering a series of 80 published studies encompassing more than 25,000 patients, the relative advantages and disadvantages of Southern blotting, polymerase chain reaction amplification, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed by immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer also are considered. The role of HER-2/neu testing for the prediction of response to Herceptin therapy in breast cancer is presented as well as its potential impact on responses to standard and newer hormonal therapies, cytotoxic chemotherapy, and radiation. The review also will evaluate the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response.

Correlation of primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate cancer.

PURPOSE: The restricted expression of the surface glycoprotein prostrate-specific membrane antigen (PSMA) to normal prostate tissue, primary and metastatic prostate cancer (PCa), and the neovasculature of various nonprostatic epithelial malignancies has enabled targeting strategies for PCa treatment using anti-PSMA antibodies. EXPERIMENTAL DESIGN: Using prostatectomy specimens, immunohistochemical staining for PSMA (7E11 antibody) was performed on formalin-fixed paraffin-embedded sections of 136 cases of PCa. Cytoplasmic immunoreactivity was scored for intensity and distribution, and results were correlated with tumor grade, pathological stage, DNA ploidy status (Feulgen spectroscopy), and disease recurrence. PSMA mRNA expression in selected primary tumors and metastatic lesions was also detected using in situ hybridization and autoradiography. RESULTS: Generally, PCa cells expressed relatively increased levels of PSMA as compared with benign elements. Among the PCa cases, increased (high) PSMA expression correlated with tumor grade (P = 0.030), pathological stage (P = 0.029), aneuploidy (P = 0.010), and biochemical recurrence (P = 0.001). The mean serum prostate-specific antigen level of 18.28 ng/ml at the time of diagnosis for the PSMA-overexpressing tumors was significantly greater than the mean serum prostate-specific antigen of 9.10 ng/ml for the non-PMSA-overexpressing group (P = 0.006). On multivariate analysis, pathological stage (P = 0.018) and PSMA expression (P = 0.002) were independent predictors of biochemical recurrence. PSMA protein overexpression in high-grade primary PCa tumors and metastatic lesions also correlated with increased PSMA mRNA expression levels using in situ hybridization and autoradiography. CONCLUSIONS: This study demonstrates for the first time that overexpression of PSMA in primary PCa correlates with other adverse traditional prognostic factors and independently predicts disease outcome.

Anticancer antibodies.

The recent clinical and commercial success of anticancer antibodies such as rituximab and trastuzumab has created great interest in antibody-based therapeutics for hematopoietic malignant neoplasms and solid tumors. Given the likelihood of lower toxic effects of antibodies that target tumor cells and have limited impact on nonmalignant bystander organs vs small molecules, the potential increased efficacy by conjugation to radioisotopes and other cellular toxins, and the ability to characterize the target with clinical laboratory diagnostics to improve the drug's clinical performance, current and future antibody therapeutics are likely to find substantial roles alone and in combination therapeutic strategies for treating patients with cancer. It also is likely that conjugation strategies will add new radiolabeled and toxin-linked products to the market to complement the recent approvals of ibritumomab tiuxetan and gemtuzumab ozogamicin. This review considers the structure of anticancer therapeutic antibodies and the techniques used to reduce their antigenicity. Efficacy and toxic effects, conjugation with isotopes and toxins, and validation of the antibody targets also are discussed. Antibodies approved by the Food and Drug Administration are described in detail, as are antibodies in late and early stages of clinical development.

Antibody-based therapeutics in oncology.

The recent clinical and commercial success of anticancer antibodies, such as rituximab (Rituxan) and trastuzumab (Herceptin) has created great interest in antibody-based therapeutics for hematopoietic malignancies and solid tumors. Given the likely lower toxicity for antibodies versus small molecules, the potential increase in efficacy by conjugation to radioisotopes and other cellular toxins and the ability to characterize the target with clinical laboratory diagnostics to improve the drug's clinical performance, it is anticipated that current and future antibody therapeutics will find substantial roles alone and in combination therapy strategies for the treatment of patients with cancer. It is also likely that conjugation strategies will add new radiolabeled and toxin-linked products to the market to complement the recent approvals of ibritumomab tiuxetan (Zevalin) and gemtuzumab ozogamycin (Mylotarg). However, although there are a large number of agents in both early and later stages of clinical development, only a handful will make it through regulatory approval and become successful products. This review considers the structure of anticancer therapeutic antibodies, the techniques used to reduce their antigenicity, factors that influence efficacy and toxicity, conjugation with isotopes and toxins and antibody target validation.